DESCRIPTION: Whereas many primary, penetrating keratoplasties succeed in humans, an intolerably high proportion fails in "high-risk" eyes. Immune rejection is the major cause of allograft failure. Our long-term goals are to understand: (a) why primary orthotopic corneal allografts are so well tolerated (display immune privilege), and (b) why grafts in "high-risk" eyes fare so poorly. During the past 5 years we have made progress toward these goals by demonstrating that: (a) MHC class II and minor H, but not MHC class I, alloantigens are important barriers to corneal allograft acceptance, (b) direct and indirect alloreactive CD4+, but not CD8+, T cells are the dominant mediators of rejection, and (c) comeal endothelium, in part through expression of CD95L, displays inherent immune privilege. Based upon these findings, we have formulated two related hypotheses to guide our experiments: Hypothesis 1. Atypical expression of alloantigens and expression of immunomodulatory molecules on corneal cells contribute to the cornea's immune privileged status. These experiments will determine if expression of alloantigens and/or immunomodulatory molecules on corneal cells, rather than the special qualities of the surrounding graft bed in the eye, contributes to the cornea's status as an immune privileged tissue. Hypothesis 2. MHC class II and/or minor H alloantigen expression rob the corneal epithelium of its graft-acceptance promoting capacity. Our previous data indicated that syngeneic epithelium makes a positive contribution to immune privilege for orthotopic corneal allografts. These experiments will utilize composite comeal grafts composed of recipient epithelium layered over donor stroma/endothelium (and visa versa). We will determine the capacity of composite corneal allografts to induce allosensitization. Our experiments will enable us to discover novel cellular and molecular mechanisms with which to create protocols with greater power to promote graft acceptance in clinical situations where graft failure is all too common.